Many previous attempts have been made to locally administer radioactive materials to patients with cancer, as a form of therapy. In some of these, the radioactive materials have been incorporated into small particles, seeds, wires and similar related configurations that can be directly implanted into the cancer. When radioactive particles are administered into the blood supply of the target organ, the technique has become known as Selective Internal Radiation Therapy (SIRT). Generally, the main form of application of SIRT has been its use to treat cancers in the liver.
There are many potential advantages of SIRT over conventional, external beam radiotherapy. Firstly, the radiation is delivered preferentially to the cancer within the target organ. Secondly, the radiation is slowly and continually delivered as the radionuclide decays. Thirdly, by manipulating the arterial blood supply with vasoactive substances (such as Angiotensin-2), it is possible to enhance the percentage of radioactive particles that go to the cancerous part of the organ, as opposed to the healthy normal tissues. This has the effect of preferentially increasing the radiation dose to the cancer while maintaining the radiation dose to the normal tissues at a lower level (Burton, M. A. et al.; Effect of Angiotensin-2 on blood flow in the transplanted sheep squamous cell carcinoma. Europ. J Cancer Clin. Oncol. 1988, 24(8):1373–1376).
When microspheres or other small particles are administered into the arterial blood supply of a target organ, it is desirable to have them of a size, shape and density that result in the optimal homogeneous distribution within the target organ. If the microspheres or small particles do not distribute evenly, and as a function of the absolute arterial blood flow, then they may accumulate in excessive numbers in some areas and cause focal areas of excessive radiation. It has been shown that microspheres of approximately 25–50 micron in diameter have the best distribution characteristics when administered into the arterial circulation of the liver (Meade, V. et al.; Distribution of different sized microspheres in experimental hepatic tumours. Europ. J. Cancer & Clin. Oncol. 1987, 23:23–41).
If the microspheres or small particles do not contain sufficient ionising radiation, then an excessive number will be required to deliver the required radiation dose to the target organ. It has been shown that if large numbers of microspheres are administered into the arterial supply of the liver, then they accumulate in and block the small arteries leading to the tumour, rather than distribute evenly in the capillaries and precapillary arterioles of the tumour.
Therefore, it is desirable to use the minimum number of microspheres that will provide an even distribution in the vascular network of the tumour circulation.
If the microspheres or small particles are too dense or heavy, then they will not distribute evenly in the target organ and will accumulate in excessive concentrations in parts of the liver that do not contain the cancer. Heavy microspheres, particularly microspheres with a density greater than about 2.3, can be difficult to deliver through infusion tubing as they settle within the tubing unless the injection force is great and the flow rate of the suspending fluid is high. High pressures and fast delivery flow rates are absolutely contra-indicated when infusing radioactive microspheres into the hepatic artery of patients as the microspheres will reflux back into inappropriate blood vessels such as the gastro-duodenal artery, splenic artery and left gastric artery. This will result in severe and even fatal consequences.
In addition, high density microspheres do not distribute evenly within the target organ and settle heterogeneously within the tissues. This, in turn, decreases the effective radiation reaching the cancer in the target organ, which decreases the ability of the radioactive microspheres to kill the tumour cells. In contrast, lighter microspheres distribute well within the liver (Burton, M. A. et al.; Selective International Radiation Therapy; Distribution of radiation in the liver. Europ. J. Cancer Clin. Oncol.1989, 25:1487–1491).
In the earliest clinical use of yttrium-90-containing microspheres, the yttrium was incorporated into a polymeric matrix that was formulated into microspheres. While these microspheres were of an appropriate density to ensure good distribution characteristics in the liver, there were several instances in which the yttrium-90 leached from the microspheres and caused inappropriate radiation of other tissues.
In one attempt to overcome the problem of leaching, a radioactive microsphere comprising a biologically compatible glass material containing a beta- or gamma-radiation emitting radioisotope such as yttrium-90 distributed homogeneously throughout the glass as one of the glass component oxides, has been developed (International Patent Publication No. WO 86/03124). These microspheres are solid high density glass and contain the element yttrium-89 as a component of the glass, which can be activated to the radionuclide yttrium-90 by placing the microspheres in a neutron beam. These glass microspheres have several disadvantages including being of a higher density than is desirable, i.e., more than 2.5 g/cm3, and containing significant amounts of other elements such as glass modifier oxides and fluxing oxides which are activated to undesirable radionuclides when placed in a neutron beam. This is as result of the glass composition used to produce the microspheres. It has also been shown in clinical studies of patients that pre-treatment imaging with technetium-99 labelled microspheres cannot be used to predict the behaviour of these solid glass microspheres. As pre-treatment imaging and dosimetry is very commonly used when treating patients with SIRT, this is a distinct disadvantage of the solid glass microspheres described in International Patent Publication No. WO 86/03124. These glass microspheres have also been shown to lodge in inappropriate tissues.
There have been several reports of clinical studies on the use of solid glass radioactive microspheres. In one report, ten patients with primary hepatocellular carcinoma were treated, however no patient had a complete or partial response (Shepherd, F. et al., Cancer, Nov. 1, 1992, Vol.70, No.9, pp 2250–2254).
Another approach has been focussed on the use of small hollow or cup-shaped ceramic particles or microspheres, wherein the ceramic base material consists or comprises yttria or the like (see International Patent Application No. PCT/AU95/00027; WO 95/19841). These microspheres were developed to overcome the high density problem associated with the solid glass microspheres.
For radioactive microspheres to be used successfully for the treatment of cancer, the radiation emitted from the microspheres should be of high energy and short range. This ensures that the energy emitted from the microspheres will be deposited into the tissues immediately around the microspheres and not into tissues which are not the target of the radiation treatment. There are many radionuclides that can be incorporated into microspheres that can be used for SIRT. Of particular suitability for use in this form of treatment is the unstable isotopes of yttrium (Yttrium-90). Yttrium-90 is the unstable isotope of yttrium-89 that can be manufactured by placing the stable yttrium-89 in a neutron beam. The yttrium-90 that is generated decays with a half life of 64 hours, while emitting a high energy pure beta radiation. Other candidate radionuclides for this invention include but are not restricted to holmium, iodine, phosphorous, iridium, rhenium, and samarium.
If the microspheres contain other radioactive substances that are not required for the radiation treatment of the target tissue, then unwanted and deleterious radiation effects may occur. It is therefore desirable to have microspheres of such a composition that they only emit radiation of the desired type to achieve the therapeutic effect. In this treatment mode, it is desirable to have microspheres that emit high energy but short penetration beta-radiation that will confine the radiation effects to the immediate vicinity of the microspheres.